The present invention relates to nucleophilic substitution of alcohols, and, especially, to fluorous nucleophilic substitution of alcohols and fluorous reagents therefor.
References set forth herein may facilitate understanding of the present invention or the background of the present invention. Inclusion of a reference herein, however, is not intended to and does not constitute an admission that the reference is available as prior art with respect to the present invention.
The Mitsunobu reaction is one of the most popular and powerful reactions in organic, synthesis and its uses range from natural products synthesis to parallel synthesis and combinatorial chemistry. See, for example, Hughes, D. L. xe2x80x9cProgress in the Mitsunobu reaction. A review.xe2x80x9d Org. Prep. Proced. Int. 1996, 28,-127-164; Hughes, D. L. xe2x80x9cThe Mitsunobu reaction.xe2x80x9d Org. React. (N.Y.) 1992; 42, 335-656; and Mitsunobu, O. xe2x80x9cSynthesis of Alcohols and Ethers.xe2x80x9d in Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.; Pergamon Press: Oxford, 1991; Vol. 6; pp 1 32. The Mitsunobu reaction is so commonly used because it allows the one-step substitution of a primary or secondary alcohol by a nucleophile. Nucleophilic substitutions of alcohols are common synthetic transformations but other general methods require two or more steps.
A traditional solution phase Mitsunobu reaction as illustrated in FIG. 1 combines an alcohol a, an acidic pro-nucleophile b, diethylazodicarboxylate c (typically referred to as xe2x80x9cDEADxe2x80x9d) and triphenylphosphine d in an organic solvent such as dichloromethane or tetrahydrofuran (THF). The reagents and reactants can be combined in different orders according to several standard procedures. The products of the reaction are the desired substitution product e, the hydrazine f derived from the reduction of c and triphenylphosphine oxide g derived from the oxidation of d. If either reagent c or d is used in excess, then this unreacted reagent may also be present. The desired product of the reaction e is typically separated from the reagent byproducts and any excess reagents by chromatography.
The need for a careful chromatographic separation is a substantial limitation of the Mitsunobu reaction. The required separation is expensive on large scale. On small scale, the time and effort needed for multiple chromatographic separations limit combinatorial and parallel applications of the reaction.
Two general approaches have been. taken to facilitate separation in Mitsunobu reactions. First, both the phosphine and the azodicarboxylate have been attached to polymeric solid phases. See, for example, Tunoori, A. R.; Dutta, D.; Georg, G. I. xe2x80x9cPolymer-Bound Triphenylphosphine as Traceless Reagent for Mitsunobu Reactions in Combinatorial Chemistry: Synthesis of Aryl Ethers from Phenols and Alcoholsxe2x80x9d Tetrahedron Lett. 1998, 39, 8751-8754; and Arnold, L. D.; Assil, H. I.; Vederas, J. xe2x80x9cPolymer-Supported Alkyl Azodicarboxylates for Mitsunobu Reactionsxe2x80x9d J. Am. Chem. Soc. 1989, 111, 3973-3976. Polymer-bound reagents and reactants can be removed from final products by simple filtration. However, in the Mitsunobu reaction, the polymer approach only solves half the problem since the two polymer-bound reagents (azodicarboxylate and phosphine) cannot be used simultaneously. These reagents must react with each other and this reaction is blocked if both are bound to polymers. So only one polymer-bound reagent can be used and the other must be a soluble reagent.
In the second approach, soluble reagents are used and then these reagents are transformed by a chemical reaction after the Mitsunobu reaction is over. See, for example, Starkey, G. W.; Parlow, J. J.; Flynn, D. L. xe2x80x9cChemically-Tagged Misunobu Reagents for Use in Solution Phase Chemical Library Synthesisxe2x80x9d Bioorg. Med. Chem. Lett., 8, 2384-89 (1998). For example, soluble phosphine and azodicarboxylate reagents with suitable functionalities can be polymerized after a Mitsunobu reaction is over and then removed by filtration. This second approach is inefficient since it requires an extra chemical reaction (with associated reagents, time and effort, etc.) which contributes only to separation and not to formation of a desired product. In addition, the desired product cannot contain any functionality that would participate in the polymerization reaction. The second approach of facilitating separation thus imposes limitations that are not imposed by a normal Mitsunobu reaction.
It is very desirable to develop improved methods for nucleophilic substitution of alcohols and reagents thereofor to, for example, reduce or eliminate the above problems with current Mitsunobu reactions.
In one aspect, the present invention provides a method of effecting a nucleophilic substitution of an alcohol to produce a target product including the steps of: reacting the alcohol and a nucleophile with an azodicarboxylate and a phosphine. At least one of the azodicarboxylate and the phosphine including at least one fluorous tag. In several embodiments, the azodicarboxylate includes at least one fluorous tag, and the phosphine includes at least one fluorous tag.
The method preferably further includes the step of separating the target product from the fluorous tagged azodicarboxylate and/or the fluorous tagged phosphine via a fluorous separation technique. The fluorous separation technique can, for example be a liquid-liquid extraction. The fluorous separation technique can also be a solid-liquid extraction. The fluorous separation technique can also be a fluorous solid phase extraction or a fluorous chromatography.
The term xe2x80x9cnucleophilexe2x80x9das used herein refers generally to an ion or a molecule that donates a pair of electrons to an atomic nucleus to form a covalent bond. Suitable nucleophiles for use in the present invention are conjugate bases of organic or inorganic acids. These acids should have a pKa preferably less than or equal to about 20, and more preferably less than or equal to about 15. Even more preferably, the pKa is less than or equal to about 12. The conjugate bases of many types of organic acids are known by those skilled in the art to be suitable for Mitsunobu reactions. Suitable nucleophiles include, but are not limited to, the conjugate bases derived from carboxylic acids, phenols, hydroxamic acids, imides, sulfonimides, sulfonamides, thiols, thioacids, thioamides, beta-dicarbonyls and assorted heterocycles. Nucleophilic conjugate bases derived from inorganic acids such as hydrogen halides or hydrogen azide, are also suitable.
Organic alcohols include a saturated carbon bonded to a hydroxyl group. Alcohols that participate in the Mitsunobu reaction are well known to those skilled in the art and include methanol and primary (for example, ethanol, propanol, allyl alcohol) and secondary (for example isopropanol and 1-phenylethanol) alcohols. Tertiary alcohols are less preferred but can still be used in some (especially intramolecular) applications.
The alcohol and the nucleophile can be in different molecules, or in the same molecule. In the later case (an intramolecular Mitsunobu reaction), a new ring is formed.
The fluorous tagged azodicarboxylate can, for example, have the formula:
Z1O2Cxe2x80x94Nxe2x95x90Nxe2x80x94CO2Z2
wherein Z, is 
In the above formula n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 are independently 1 or 0. X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X13, X14, X15, X16, X17, X18, X19 and X20 are independently H, F, Cl, an alkyl group, an aryl group or an alkoxy group. R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 are indenpendently H, F, Cl, an alkyl group, an alkoxy group, a thioalkyl group, a dialkylamino group, a nitro group, a cyano group, a perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group, a fluorinated amine group, Oxe2x80x94Rf1, Sxe2x80x94Rf2, or xe2x80x94N(Rf3)(R22), wherein R22 is an alkyl group or Rf4, and wherein Rf4, Rf2, Rf3 and Rf4 are independently a fluorous group selected from the group of a perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group, or a fluorinated amine group. At least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 or R16 is Oxe2x80x94Rf1, Sxe2x80x94Rf2, xe2x80x94N(Rf3)(R22), a perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group or a fluorinated amine group.
Perfluoroalkyl groups are preferably of 3 to 20 carbons. Hydrofluoroalkyl groups are preferably of 3 to 20 carbons and include up to one hydrogen atom for each two fluorine atoms. For example, perfluorinated ether groups can have the general formula xe2x80x94[(CF2)xO(CF2)y]zCF3, wherein x, y and z are integers. Perfluorinated amine groups can, for example, have the general formula xe2x80x94[(CF2)xxe2x80x2(NRa)CF2)yxe2x80x2]zxe2x80x2CF3, wherein xxe2x80x2, yxe2x80x2 and zxe2x80x2 are integers and wherein Ra can, for example, be CF3 or (CF2)nxe2x80x2CF3 wherein nxe2x80x2 is an integer. Fluorinated ether groups and fluorinated amine groups suitable for use in the present invention need not be perfluorinated, however. Fluorinated ether groups are preferably of 3 to 20 carbons. Fluorinated amine groups are preferably of 4 to 20 carbons.
The fluorous tagged phosphine can, for example, have the formula 
wherein Z3 is 
In the above formula R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16, R17, R18, R19, R20, and R21 are independently H, F, Cl, an alkyl group, an alkoxy group, a thioalkyl group, a dialkylamino group, a nitro group, a cyano group, a perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group, a fluorinated arnine group, Oxe2x80x94Rf1, Sxe2x80x94Rf2, xe2x80x94N(Rf3)(R22), wherein R22 is an alklyl group or Rf4, and wherein Rf1, Rf2, Rf3 and R4 are independently a fluorous group selected from the group of a perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group or a fluorinated amine group. At least one of R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20 and R21 is Oxe2x80x94Rf1, Sxe2x80x94Rf2, xe2x80x94N(Rf3)(R22), perfluoroalkyl group, a hydrofluoroalkyl group, a fluorinated ether group or a fluorinated amine group.
Once again, perfluoroalkyl groups are preferably of 3 to 20 carbons and hydrofluoroalkyl groups are preferably of 3 to 20 carbons. Hydrofluoroalkyl groups preferably include up to one hydrogen atom for each two fluorine atoms.
The alcohol upon which a nucleophilic substitution is effected is preferably a primary alcohol or a secondary alcohol. The alcohol and the nucleophile can, for example, be added to a mixture of the fluorous tagged azodicarboxylate and the fluorous tagged phosphine.
In another aspect, the present invention provides a compound having the formula
Z1O2Cxe2x80x94Nxe2x95x90Nxe2x80x94CO2Z2
wherein Z1 and Z2 are as defined above.
In another aspect, the present invention provides a compound having the formula 
wherein Z1 and Z2 are as defined above.
In still a further aspect, the present invention provides a method of synthesizing a compound having the formula:
Z1O2Cxe2x80x94Nxe2x95x90Nxe2x80x94CO2Z2
comprising the step reacting a compound having the formula: 
(wherein Z1 and Z2 are as defined above) with an oxidant. In one embodiment, the oxidant is dibromine.
In several embodiments of the present invention Z1 and Z2 are Rf(CH2)Nxe2x80x94, wherein N is an integer in the range of 1 to 5 and Rf is a perfluoroalkyl group. Preferably, the perfluoroalkyl group is of 3 to 20 carbons. In several embodiments, linear perfluoroalkyl groups of 3 to 20 carbons were present.
As used herein, the terms xe2x80x9cproductxe2x80x9d or xe2x80x9ctarget productxe2x80x9d refer generally to the target or desired molecule(s) of the nucleophilic substitution of the substrate alcohol resulting from reaction of the substrate alcohol with the other reaction component(s) of the present invention in a reaction medium. The terms xe2x80x9cside productxe2x80x9d or xe2x80x9cbyproductxe2x80x9d refer generally to a product derived from any component(s) of the reaction medium which is not the target product and is preferably separated therefrom.
As used herein, the ternms xe2x80x9cfluorous taggingxe2x80x9d or xe2x80x9cfluorous taggedxe2x80x9d refer generally to attaching a fluorous moiety or group (referred to as a xe2x80x9cfluorous tagging moiety,xe2x80x9d xe2x80x9cfluorous tagging groupxe2x80x9d or simply xe2x80x9cfluorous tagxe2x80x9d) to a compound to create a xe2x80x9cfluorous tagged compoundxe2x80x9d. Preferably, the fluorous tagging moiety is attached via covalent bond. However, other strong attachments such as ionic bonding or chelation can also be used. In the present invention, fluorous tagging moieties are preferably used on different compounds to facilitate separation of fluorous tagged compounds from, for example, untagged organic compounds.
As used herein, the term xe2x80x9cfluorousxe2x80x9d, when used in connection with an organic (carbon-containing) molecule, moiety or group, refers generally to an organic molecule, moiety or group having a domain or a portion thereof rich in carbon-fluorine bonds (for example, fluorocarbons, fluorohydrocarbons, fluorinated ethers and fluorinated amines). The terms xe2x80x9cfluorous tagged reagentxe2x80x9d or xe2x80x9cfluorous reagent,xe2x80x9d thus refer generally to a reagent comprising a portion rich in carbon-fluorine bonds. As used herein, the term xe2x80x9cperfluorocarbonsxe2x80x9d refers generally to organic compounds in which all hydrogen atoms bonded to carbon atoms have been replaced by fluorine atoms. The terms xe2x80x9cfluorohydrocarbonsxe2x80x9d and xe2x80x9chydrofluorocarbonsxe2x80x9d include organic compounds in which at least one hydrogen atom bonded to a carbon atom has been replaced by a fluorine atom. The attachment of fluorous moieties to organic compounds is discussed for example, in U.S. Pat. Nos. 5;859,247, 5,777,121 and U.S. patent application Ser. No. 09/506,779, and U.S. Provisional Patent Application Serial No. 60/281,646, assigned to the assignee of the present invention, the disclosures of which are incorporated herein by reference.
The terms xe2x80x9calkylxe2x80x9d, xe2x80x9carylxe2x80x9d and other groups set forth herein refer generally to both unsubstituted and substituted groups unless specified to the contrary. Unless otherwise specified, alkyl groups are hydrocarbon groups and are preferably C1-C15 (that is, having 1 to 15 carbon atoms) alkyl groups, and more preferably C1-C10 alkyl groups, and can be branched or unbranched, acyclic or cyclic. The above definition of an alkyl group and other definitions apply also when the group is a substituent on another group (for example, an alkyl group as a substituent of an alkylamino group or a dialkylamino group). The term xe2x80x9carylxe2x80x9d refers to phenyl or naphthyl, and preferably phenyl. The term xe2x80x9calkoxyxe2x80x9d refers to xe2x80x94ORa, wherein Ra is an alkyl group.
Separation of the compounds in the present invention is preferably achieved by using separation techniques that are complementary to (based upon differences between) the fluorous content. Compounds differing in fluorous content can be separated using a fluorous separation technique (for example, fluorous reverse phase chromatography). As used herein, the term xe2x80x9cfluorous separation techniquexe2x80x9d refers generally to a method that is used to separate mixtures containing fluorous tagged molecules (or fluorous molecules) and organic (non-fluorous) molecules based predominantly on the difference in fluorous nature of molecules. Fluorous separation techniques include but are not limited to chromatography over solid fluorous phases such as fluorocarbon bonded phases or fluorinated polymers. See, for example, Danielson, N. D. et al., xe2x80x9cFluoropolymers and Fluorocarbon Bonded Phases as Column Packings for Liquid Chromatography,xe2x80x9d J. Chromat., 544, 187-199 (1991); Kainz, S., Luo, Z. Y., Curran, D. P., Leitner, W., xe2x80x9cSynthesis of Perfluoroalkyl-Substituted Aryl Bromides and Their Purification Over Fluorous Reverse Phase Silicaxe2x80x9d, Synthesis, 1425-1427 (1998); and Curran, D. P., Hadida, S., He, M., xe2x80x9cThermal Allylations of Aldehydes with a Fluorous Allylstannane. Separation of Organic and Fluorous Products by Solid Phase Extraction with Fluorous Reverse Phase Silica Gelxe2x80x9d, J. Org. Chem., 62, 6714-6715 (1997). Examples of suitable fluorocarbon bonded phases include commercial Fluofix(copyright) and Fluophase(trademark) columns available from Keystone Scientific, Inc. (Bellefonte, Pa.), and FluoroSep(trademark)-RP-Octyl from ES Industries (Berlin, N.J.). Other fluorous separation techniques include liquid-liquid based separation methods such as standard separatory-funnel type extractions and countercurrent distribution with a fluorous solvent and an organic solvent.
The process of separation of the fluorous tagged reagents and byproducts of the present invention from the organic target product and other organic species takes only a few minutes and can be readily conducted in parallel, so it is highly suitable not only for individual reactions but also for combinatorial chemistry experiments with parallel reactions. The fluorous Mitsunobu reaction of the present invention is also economical since the mixture of fluorous byproducts can be readily separated and each of the products can be reconverted to the corresponding original fluorous reagents by standard chemical reactions.
In common organic synthesis, individual steps are conducted sequentially until the final target molecule or product is made. In combinatorial organic synthesis, the target is not a single molecule but instead a xe2x80x9clibraryxe2x80x9d of molecules. Combinatorial synthesis can be carried out by parallel synthesis of individual pure compounds or synthesis of mixtures.
In mixture and combinatorial synthesis, multiple reactions are conducted either together or in parallel to provide multiple products. In mixture synthesis and combinatorial synthesis, the premium of simple methods of purification is even higher than in normal synthesis. For this reason, combinatorial synthesis is now commonly conducted on the solid phase, where purification can be effected simply by filtration. However, conducting such reactions can be difficult because the solid-bound reaction component never truly dissolves in the reaction solvent.